In situ mass spectrometry imaging reveals heterogeneous glycogen stores in human normal and cancerous tissues

Lyndsay E.A. Young, Lindsey R. Conroy, Harrison A. Clarke, Tara R. Hawkinson, Kayli E. Bolton, William C. Sanders, Josephine E. Chang, Madison B. Webb, Warren J. Alilain, Craig W. Vander Kooi, Richard R. Drake, Douglas A. Andres, Tom C. Badgett, Lars M. Wagner, Derek B. Allison, Ramon C. Sun, Matthew S. Gentry

Research output: Contribution to journalArticlepeer-review

Abstract

Glycogen dysregulation is a hallmark of aging, and aberrant glycogen drives metabolic reprogramming and pathogenesis in multiple diseases. However, glycogen heterogeneity in healthy and diseased tissues remains largely unknown. Herein, we describe a method to define spatial glycogen architecture in mouse and human tissues using matrix-assisted laser desorption/ionization mass spectrometry imaging. This assay provides robust and sensitive spatial glycogen quantification and architecture characterization in the brain, liver, kidney, testis, lung, bladder, and even the bone. Armed with this tool, we interrogated glycogen spatial distribution and architecture in different types of human cancers. We demonstrate that glycogen stores and architecture are heterogeneous among diseases. Additionally, we observe unique hyperphosphorylated glycogen accumulation in Ewing sarcoma, a pediatric bone cancer. Using preclinical models, we correct glycogen hyperphosphorylation in Ewing sarcoma through genetic and pharmacological interventions that ablate in vivo tumor growth, demonstrating the clinical therapeutic potential of targeting glycogen in Ewing sarcoma.

Original languageEnglish
Article numbere16029
JournalEMBO Molecular Medicine
Volume14
Issue number11
DOIs
StatePublished - Nov 8 2022

Bibliographical note

Funding Information:
We would like to thank Mrs. Dana Napier for performing histological staining on tissue slices, and the Markey Cancer Center. This study was supported by the National Institute of Health (NIH) grants R35 NS116824 (MSG), P01 NS097197 (MSG), NIH grant R01 AG066653 (RCS), NIH grant R01 R01CA266004 (RCS), NIH/NCI F99CA264165 (LEAY), NIH/NCI training grant T32CA165990 (LRC), St Baldrick's Career Development Award (RCS), V‐Scholar Grant (RCS), Rally Foundation Independent Investigator Grant to (RCS), and Cure Alzheimer's Fund (RCS). This research was also supported by funding from the University of Kentucky Markey Cancer Center and the NIH‐funded Biospecimen Procurement & Translational Pathology Shared Resource Facility of the University of Kentucky Markey Cancer Center P30CA177558.

Publisher Copyright:
© 2022 The Authors. Published under the terms of the CC BY 4.0 license.

Keywords

  • Ewing sarcoma
  • MALDI imaging
  • glycogen
  • glycogen storage disease
  • spatial metabolism

ASJC Scopus subject areas

  • Molecular Medicine

Fingerprint

Dive into the research topics of 'In situ mass spectrometry imaging reveals heterogeneous glycogen stores in human normal and cancerous tissues'. Together they form a unique fingerprint.

Cite this